Interferons (hereinafter “interferon” is sometimes abbreviated as IFN) are the most important cytokines in antiviral immune response. An interferon-producing cell (IPC: IPC is an undifferentiated lymphocytic dendritic cell that is positioned as a precursor cell of a dendritic cell (DC). IPC is also sometimes called a plasmacytoid dendritic cell or a plasma cell-like dendritic cell (plasmacytoid dendritic cell: pDC). Hereinafter IPC and pDC are considered to have the same meaning herein, and are hereinafter standardized by the term pDC as a general rule.) in human blood expresses a major histocompatibility complex Class II protein together with CD4. However, since the number of such cells is small and the cells rapidly cause apoptosis and lack a lineage marker, those cells have not been isolated or characterized in detail until now. It was proved that pDC is a CD4+CD11c-2-type dendritic cell precursor cell, and that it produces IFN by 200 to 1,000 times greater than that produced by other blood cells after stimulation by a microorganism. Therefore, pDC2 is a decisive immune system effector cell in antiviral and antitumor immune responses.
IFNα and IFNβ are known as Type I IFNs having an antiviral activity or antitumor activity. On the other hand, it was clarified that IFNα relates to autoimmune diseases. For example, abnormal production of IFNα was reported in patients suffering from the following autoimmune diseases. Furthermore, possibility of alleviation of an autoimmune condition by neutralizing IFNα was suggested.
Systemic erythematosus (Shiozawa et al., Arthr. & Rheum. 35, 412, 1992) and chronic rheumatoid arthritis (Hopkins et al., Clin. Exp. Immunol 73, 88, 1988), and furthermore, examples in which a condition of an autoimmune disease was expressed or deteriorated by administering recombinant IFNα2 or IFNβ were reported (Wada et al., Am. J. Gastroenterol. 90, 136, 1995; Perez et al., Am. J. Hematol. 49, 365, 1995; Wilson L E et al., Semin Arthritis, Rheum. 32, 163-173, 2002).
Furthermore, it was also clarified that IFNα induces the differentiation of a dendritic cell (DC). Since a dendritic cell is also an antigen presenting cell, it is considered that the induction of differentiation of a dendritic cell constitutes an important mechanism in autoimmune diseases. In fact, it was suggested that the induction of differentiation of a dendritic cell of IFNα is intimately related to the onset of systemic erythematosus (Blanco et al., Science, 16: 294, 1540-1543, 2001). Therefore, the antitumor activity and intimate relation with autoimmune diseases of IFNα have been pointed out. Furthermore, IFNα also intimately relates to the onset of psoriasis (Nestle F O et al., J. Exp. Med. 202, 135-143, 2005).
Only a small amount of pDC is present in blood. It is considered that the ratio of pDC in peripheral blood lymphocyte is 1% or less. However, pDC has an extremely high ability of producing IFN. The ability of pDC to produce IFN reaches, for example, 3,000 pg/mL/104 cells. Namely, it can be considered that, although the number of cells is small, the major part of IFNα or IFNβ in blood is produced while viral infection is brought by pDC.
pDC differentiates into a dendritic cell by viral stimulation to induce the production of IFN-γ and IL-10 by a T cell. Furthermore, pDC also differentiates into a dendritic cell by the stimulation of IL-3. The dendritic cell differentiated by the stimulation of IL-3 induces the production of Th2 cytokines (IL-4, IL-5, IL-10) by a T cell. Thus, pDC has a characteristic that it differentiates into different dendritic cells depending on the difference of stimulation.
Therefore, pDC is a cell having two aspects: one is an aspect as an IFN-producing cell and other is an aspect as a precursor cell for a dendritic cell. Both cells play important roles in an immune system. Namely, pDC is one of important cells that support an immune system from various aspects.
For the control of the activity of a humoral factor such as IFN, administration of an antibody that recognizes the factor is effective. For example, an attempt to treat an autoimmune disease by an antibody against interleukin (IL)-1 or IL-4 was put to practical use (Guler et al., Arthritis Rheum, 44, S307, 2001). Furthermore, it is considered that a neutralized antibody may become a therapeutic drug for autoimmune diseases also in interferons (IFNs) (Stewart, T A. Cytokine Growth Factor Rev. 14; 139-154, 2003). It can be expected that a similar approach would be effective for IFNs produced by pDC. However, such approach is based on the inhibition of the action of the produced humoral factor. If the production of an objective humoral factor can be controlled directly, a more essential therapeutic effect can be achieved.
An antibody that recognizes human pDC was reported. For example, an anti-BDCA-2 monoclonal antibody is a monoclonal antibody that is specific to human pDC (Dzionek A. et al., J. Immunol 165: 6037-6046, 2000). It was clarified that the anti-BDCA-2 monoclonal antibody has an action of suppressing the IFN production of human pDC (J. Exp. Med. 194: 1823-1834, 2001). Furthermore, it was also reported that a monoclonal antibody that recognizes a mouse interferon-producing cell suppresses the production of interferons (Blood 2004 Jun. 1; 103/11: 4201-4206. Epub 2003 December). It was reported that a monoclonal antibody against mouse pDC decreased the number of dendritic cells (J. Immunol. 2003, 171: 6466-6477).
It is useful if an antibody that similarly recognizes human pDC and may control the activity thereof is provided. For example, the present inventors have already clarified that an antibody that recognizes Ly49Q specifically binds to mouse pDC. However, an antibody against Ly49Q did not interfere the activity of mouse pDC (Blood, 1 Apr. 2005, vol. 105, No. 7, pp. 2787-2792: WO2004/13325A1).
Protein phosphatases are dephosphorylated enzymes that were found in the studies of glycogen metabolism. Besides protein tyrosine phosphatase (PTP), protein serine/threonine phosphatase, phospholipid-specific phosphatase and the like have been found, and these form a superfamily of protein phosphatases. Of these, protein tyrosine phosphatase is an enzyme that is responsible for phosphorylation among reversible phosphorylation modifications that are observed in tyrosine residues of proteins. On the other hand, protein tyrosine kinase (PTK) is exemplified as an enzyme that is responsible for phosphorylation among reversible phosphorylation modifications that are observed in tyrosine residues of proteins.
Protein tyrosine phosphatase (PTP) converts the binding information of a ligand in an extracellular domain thereof to the phosphatase activity of an intracellular domain, and it is considered that protein tyrosine kinase (PTK) is activated by the binding of a ligand, whereas protein tyrosine phosphatase (PTP) is generally inactivated by the binding of a ligand. Therefore, in both of protein tyrosine phosphatase (PTP) and protein tyrosine kinase (PTK), stimulation of a ligand leads to increase in the phosphorylation level, whereas a great difference is expected in the signal properties. In the case of protein tyrosine kinase (PTK), positive feedback control in which receptors are phosphorylated with each other and activated is conducted, and the topical activation of the protein tyrosine kinase (PTK) molecules transmits to other protein tyrosine kinase (PTK) molecules on a cell membrane, thereby phosphorylation is increased over a wide range. On the other hand, only molecules to which ligands have bound are inactivated in protein tyrosine phosphatase (PTP), and the phosphorylation of the substrate is increased only topically. Protein tyrosine phosphatase (PTP) that is involved in many physiological functions and cellular functions gets a lot of attention in broad areas of brain neurobiochemistry, immunology, cancers, diabetes mellitus and the like (copy of the home page of the Division of Molecular Neurobiology, National Institute for Basic Biology, http://niwww3.nibb.acjp/RPTP.pdf).
The protein tyrosine phosphatase family can be classified into a receptor type having a cell membrane penetrating region and a non-receptor type. There are 21 molecules of receptor type protein tyrosine phosphatases (also abbreviated as RPTP or PTPR) in mammals, which are classified into eight subfamilies and each subfamily has an inherent extracellular structure in which a immunoglobulin-like domain, a fibronectin type III-like domain, a carbonate dehydratase-like domain, an MAM domain and the like are observed (Nat Rev Mol Cell Biol., Vol. 7, 833-846, 2006).
Human receptor-type protein tyrosine phosphatase σ (this is abbreviated as hRPTP-σ, hPTP-σ or hPTPRS, and the abbreviation hPTPRS that is mainly used herein) belongs to a R2A subfamily together with LAR (leukocyte antigen-related protein tyrosine phosphatase) and receptor-type protein tyrosine phosphatase δ (PTP-δ). Enzymes of the PTPR family are expressed in various tissues including nerve systems from initiation of generation to after maturation of animals, but few physiological functions thereof have been clarified since identification of ligand molecules and substrate molecules is not easy.
Dendritic cells (DCs) are major antigen presenting cells in a living body, which are present in blood, lymphoid tissues and the like and are roughly classified into myeloid dendritic cell (mDCs) and plasmacytoid dendritic cells (pDCs). pDC selectively expresses TLR7 and TLR9 as Toll-like receptors on the cell surfaces thereof, and produce Type I interferons α and β, specifically interferon α.
The recent studies have clarified various ligand molecules that act on dendritic cells to control their maturation and activation, and the intracellular signal transmission mechanisms from the receptors thereof have been becoming clear. However, there are many unclear points about the mechanisms of modification and control of the functions of dendritic cells. Similarly to the clarification in many other cells, it is considered that the phosphorylation of proteins plays an important role also in dendritic cells for the control of signal transmission from receptors, of motion/migration of cells, and the like.
Protein phosphatases that are negative controlling factors for protein phosphorylation are dominant candidates as factors for maintaining suitable intensities and lengths of signals to modulate the activation and functions of dendritic cells. (Nobuhiro Tanuma (Institute for Genetic Medicine, Hokkaido University), “Functional Analysis Of Tyrosine Phosphatase Induced in Maturing of Dendritic Cells” in the homepage of the Northern Advancement Center for Science & Technology (abbreviation: NOASTEC), http://www.noastec.jp/kinouindex/data2005/pdf/01/01_20.pdf)
International Publication No. WO95/9656A1 discloses RPTP-σ (PTPRS) and a nucleic acid coding therefor; however, the disclosed amino acid sequence is one derived from a rat, and the publication does not mention about an antibody specific to PTPRS. International Publication No. WO95/9656A1 also fails to disclose about an anti-human PTPRS antibody.
International Publication No. WO2007/41317A1 relates to an isolated antibody that specifically binds to at least RPTP-σ or RPTP-δ to suppress the immune response of an immune cell, or an antigen binding fragment thereof. The document describes that the binding of poxvirus polypeptide A41L and RPTP is competitively inhibited by using an antibody that specifically binds to RPTP, thereby suppression of the immune response of an immune cell is achieved. However, this document fails to disclose that the antibody that specifically binds to RPTP-σ (PTPRS) was actually obtained, and as far as the description of the Examples is called into account, the Examples merely confirmed that RPTP expressed in an immune cell that binds to A41L is a part of RPTP-σ, RPTP-δ and LAR that belong to the same subtype R2A and prepared a fusion protein of the immunoglobulin-like domain of LAR and Fc (LAR (Ig domain)-Fc fusion protein). It is hardly to say that International Publication No. WO2007/41317A1 discloses an antibody specific to only RPTP-σ and the preparation therefor.
An antibody that binds to only RPTP-σ, i.e., the specific site of PTPRS in the present application and an antibody that may specifically bind to RPTP-σ (PTPRS) but not to RPTP-δ and LAR that belong to the same subtype R2A have not been obtained yet. Human PTPRS is a molecule whose specific expression in pDC is observed, but any antibody against human PTPRS has not been obtained up until now.